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A View from the Bench: An Interview with Dr. Patricia Steeg

Molecular biologist Patricia Steeg is Chief of the Women's Cancers Section, at the Center for Cancer Research, National Cancer Institute. She directs our Center of Excellence that is studying breast cancer brain metastases.

Recently, Dr. Steeg was awarded the 2008 Komen Brinker Award for Scientific Distinction - the highest honor conferred by Susan G. Komen for the Cure. Dr. Steeg is being recognized for her work in tumor metastasis, identifying the first metastasis suppressor gene and bringing this research to clinical trial, as well as pioneering work on brain metastasis of breast cancer.

We talked with Dr. Steeg about her work in brain metastasis, the goals of her research and how the idea for the Center of Excellence became a reality.

Musa Mayer: How did you get involved in this field of inquiry?

Pat Steeg: Iâ€™ve been studying metastasis for twenty years, and Iâ€™ve seen it progress from a field that was strictly cell biology to a field where we have some molecular understanding. Itâ€™s only been in the last five to ten years that weâ€™ve really focused on site-specific metastasis. The brain was essentially unknown in this field.

The long story is that a researcher from Germany asked me a question at a research symposium about what stimulates brain metastases, and I was able to tell him that we know this is important, and we know that the incidence is increasing, but we donâ€™t know anything else, because we have no resources. We have no mouse models, and we certainly have no tissues. We knew nothing. When this surgery resident came up to me and said that he had all of six tissues, I immediately realized that this was six more than the rest of the world had put together, and that we had an opportunity to investigate something important which had barely been touched by anybody else.

When I delved into it, the first hints were coming out that brain mets were increasing in incidence, particularly in women with HER2-positive disease, and I realized that this was going to be what is called a â€śsanctuary site,â€ť which is a metastatic site that eludes treatment and was going to give nothing but trouble down the road.

MM: Having found this potentially unexplored area, what did you do next?

PS: I give seminars all the time on metastasis suppressor genes. So everywhere I went, I asked if they had a department of neurosurgery. I would ask to have an hour meeting with the chair of neurosurgery, and I would walk in and say, â€śI donâ€™t know anything about your field, but Iâ€™m interested in it, and hereâ€™s what I want to do.â€ť I was looking mostly for tissue, for neurosurgery departments that had managed to freeze a portion of resected brain metastasis from breast cancer. Most institutions looked at me and said, â€śNo, we donâ€™t have any.â€ť A couple of them said, â€śOh, we have one or two, I think, somewhere in the freezer.â€ť To my delight, one institution said, â€śYes, we have 123 of them.â€ť This was the beginning of putting the team together.

The other part of the team had to come from studying the blood-brain barrier, because we knew almost nothing about it. The supposition was that the blood-brain barrier clearly was intact normally, and it severely limits what can cross over into the brain. Most chemotherapeutics simply will not cross. The supposition was that when a metastatic tumor cell traversed the blood-brain barrier, it could re-knit itself and remain intact, but that once a metastasis formedâ€”a big metastasis that you could see on imagingâ€”that the blood-brain barrier had been broken, and that to some extent, drugs would get in. But this was all supposition. To my knowledge, there was one mouse study where they injected a dye and looked at the percentage of lesions that took up the dye. But that was one dye of one molecular weight and one chemical structure. We knew nothing about how drugs penetrated what I now call the blood-tumor barrier, the blood-tumor barrier in a micromet (micrometastasis), or in a clinical tumor metastasis, and the heterogeneity between different micromets, or between different clinical metastases.

So the second part of the search was to find researchers who understood the blood-brain barrier. I was very lucky to find Quentin Smith and Paul Lockman at Texas Tech, who had been working on nicotine addiction, and who had also done some work in cancer. I was able to recruit them to set up our model system and to learn from it what the permeability [of the blood-brain barrier] is. These data are just starting to come out now, and they are absolutely fascinating.

The third part of organizing the Center of Excellence was to establish some pre-clinical model systems that we could use for molecular work and preclinical therapeutics, and that was work that we mostly did in house at the NCI, although I was able to recruit very experienced animal modelers: Anne Chambers, who is world-famous for her studies on imaging and dormancy, and Janet Price, who has done exquisite work on animal models.

With that, you could see the pieces [of the Center of Excellence] start to come together. We filled it out with a series of breast cancer molecular biologists and oncologists who had good leads (for therapeutics) that they then wanted to ask: Does this apply to breast cancer? From the clinicians, we needed perspective. The major question is: do we concentrate on the therapeutics that are currently available, or do we need to start over, and get ourselves a new toolbox of therapeutics that did not come down the same road of development in breast cancer but were developed based on blood-brain barrier permeability and then tested for possible efficacy in brain metastases.

The last component is that we wanted to run a Phase I pre-surgical clinical trial, and so I recruited a neurosurgeon and an oncologist at Cleveland Clinic who would actually propose and run this clinical trial.

An advocate was at the start of this process, and that was Marlene McCarthy of the NBCC. I told her that I had just laid hands on those six tissues. She immediately saw the value of the project and encouraged me strongly. It was because of her overwhelming reaction that I didnâ€™t just give up, because I felt I had committed myself. You have a lot of good ideas, but actually making them work is the hard part. There was something in Marleneâ€™s reaction when I initially mentioned this, that I felt committed to it. I then recruited Musa Mayer who helped me every step of the way in vetting proposed candidates for the COE and vetting the hypotheses, the goals, we would go after. Musa then recruited Helen Schiff, who has extraordinary experience in patient outreach.

MM: The start date of the Center of Excellence was May, 2006. What has been accomplished in the first year and a half?

PS: First and foremost, we now have an animal model. We have a quantitative animal model that we can use to test molecular biology leads and drugs. We have collected tissues and they are being worked up, for gene expression analysis. Weâ€™ve put together a clinical trial protocol. The most exciting thing Iâ€™ve seen is that Paul and Quentin have adapted the model system to begin to determine drug levels in micrometastases and clinical metastasesâ€”and the preliminary data is not what we expected. Itâ€™s going to lead to major revisions in our thinking. We have identified what we think are dormant [cancer] cells in the brain, which opens up another whole new area of thinking. We have preclinically validated lapatinib as having preventative ability against metastatic colonization in the brain.

MM: Where do you hope this research is going?

What I envision is a new approach to clinical testing of agents for therapy of brain metastases in breast cancer. I think that we will have multiple model systems very soon, that we will be able to vet these potential drugs in, and that we will know not only the biology but the pharmacology. I think we will eventually form a mini-cooperative group of clinicians who are going to specialize in this type of trial. We will clearly explore not only drugs, but drugs and radiation, and quality of life.

MM: Do you see implications for other cancers that metastasize to the brain?

We are generating interest. We are getting plenty of calls from the lung cancer community, because they have the highest incidence of brain metastasis. They are very interested in developing similar models. Weâ€™re also hearing from melanoma investigators.